Adjusting Europe's drug regulation to public health needs

Adjusting Europe's drug regulation to public health needs

VIEWPOINT Viewpoint Adjusting Europe’s drug regulation to public health needs Silvio Garattini, Vittorio Bertele’ The inauguration of the European M...

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VIEWPOINT

Viewpoint

Adjusting Europe’s drug regulation to public health needs Silvio Garattini, Vittorio Bertele’ The inauguration of the European Medicines Evaluation Agency (EMEA) 5 years ago, revolutionised the European pharmaceutical system. The new system saves member states of the European Union time and effort in assessing marketing authorisation applications, and ensures a homogeneous regulatory policy throughout the European Union. Pharmaceutical companies apply only once for marketing authorisations, extensions, and variations; thus they avoid the uncertainty caused in the past by different procedures and bureaucracies in the 15 member states. However, harmonisation is far from complete because prices and reimbursability of products are left to individual member states, which have different health systems. CPMP (Committee for Proprietary Medicinal Products), the scientific advisory committee, and EMEA’s technical and administrative staff have made the new system efficient and reliable: 126 products (98 active ingredients) have been positively assessed and released for marketing by the European Commission. EMEA’s merits are undisputed and its effect on the pharmaceutical area rightly acknowledged. However, some aspects of the system need to be reviewed to ensure that patients derive maximum advantage.

Institutional location of EMEA EMEA is located in an industrial institution of the European Commission (initially called Directorate General [DG] III, now called DG Enterprise) despite the fact that its mission is “to promote the protection of human health . . . and of consumers of medicinal products”.1 Public health should be the fundamental concern of EMEA because it is the final outcome of improved availability of medicines. The pharmaceutical industry aims to enlarge its market to maximise profits. Consumers, who are frequently anxious to have access to drugs even while they are still in an early stage of assessment, can be biased in assessing the merit of therapies. If public health issues were paramount, EMEA approval of new drugs would depend on their benefit to patients, and would be granted only for well defined indications after extensive research. Removal of EMEA from its industrial location would therefore indicate political willingness to think of patients as more important than the interests attached to the production of medicines.

How EMEA is financed Financial support for EMEA comes from two sources: a European Community grant, and the fees EMEA charges industry for the assessment of dossiers and other services.1 EMEA is forced to compete with national agencies for Lancet 2001; 358: 64–67 Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy (Prof S Garattini MD, V Bertele’ MD) Correspondence to: Prof S Garattini (e-mail: [email protected])

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these fees, because—apart from biotechnology products— industry can apply to these agencies via the decentralised procedure, and hope to obtain approval with greater ease than through the EMEA. To eliminate this conflict, all applications for the European market should be made to one agency, the EMEA. EMEA should be allowed to do its own research (or to contract research out to third parties) to confirm or disprove data reported by industry. EMEA should also be equipped to deal with pharmacovigilance, to review drug use, and to make active investigations rather than relying on spontaneous reports and secondhand data. Europe should acknowledge the need for the EMEA to take on these new roles, and supply the substantial investment that they would require. EMEA is still much smaller than the US Food and Drug Administration, although it covers almost double the population of its transatlantic cousin. If the European Community’s grant were adequate, fees paid to EMEA by industry would be a small proportion of its income, and allow the agency to be free and independent.

Membership of CPMP The composition of CPMP is not homogeneous. All CPMP members are nominated by national authorities, but some are delegates of national drug evaluation agencies who maintain good relations with their organisations, and some are independent experts who provide a further level of critical analysis in approval and monitoring of new drugs. Each member state of the European Union should nominate one independent expert and one staff member from its drug evaluation agency, to provide a broader picture that combines scientific and regulatory views.

Scientific advice, opinions, and appeals It is unusual for the same organisation and especially the same individuals—ie, CPMP members—to advise industry about the best way to develop a drug, to decide on approval of that drug, and, in appeal cases, to decide on approval for a second time. Scientific advice should not be a systematic activity, and should be given more on the CPMP’s initiative than at the request of companies.1 If the CPMP were to give a negative opinion on a drug, it should not be able to change its opinion on the same dossier within a mere 120 days. Appeals should only be possible for serious reasons, such as deliberate misuse of information in the dossier. The appeal should be judged by an independent group of experts who come from outside the CPMP. Assessment of the dossiers could also be improved. One of the two CPMP rapporteurs is normally suggested by the company.1,2 This situation is difficult to condone. A company would be unlikely to select its rapporteur from CPMP members who are thought to be critical. In addition, a report by an independent expert is a required part of the dossier.3 In practice, these “neutral” experts tend to extol the virtues of the new drug rather than give a

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VIEWPOINT

balanced view of its pros and cons. A summary of the dossier prepared by the company would be a less hypocritical document. All the reports at all stages are made available to the companies involved, which is an unnecessary level of transparency. The reports by the two rapporteurs are only preparatory material for the final document, which is the assessment report approved by the CPMP. Therefore, only this final document should be made available to the company. More time in the assessment procedure is allowed to companies than to the CPMP. Industry can stop the procedure several times, for several months if required, but the CPMP must follow a rigid schedule.2 The CPMP should be allowed equal flexibility in the timing of the assessment process.

Objectives of assessment Quality, safety, and efficacy European Union legislation4 repeatedly states that drugs should be assessed for their quality, efficacy, and safety. However, this statement has been interpreted and acted on as if each drug were to be made available in a therapeutic vacuum. Industry has determined that once quality is acceptable, efficacy is suggested even if not shown, and safety raises no serious concerns—any drug should be allowed on the market. The apparent aim of industry is to produce a European catalogue from which physicians, or even in some cases patients, can select which medicine to use, and national health services can select drugs to be reimbursed. However, if there is no way of making valid comparisons between products, how can physicians or patients make informed choices? This point is made in several guidelines, including the E10 document5 of the International Conference for Harmonisation last year, that medicines should be tested against comparative drugs rather than placebos. These guidelines generated a strong reaction from the European Federation of Pharmaceutical Industries and Associations, which stated that for legal, scientific, and public-health reasons “quality, safety, and efficacy must remain the only criteria to assess the applications for marketing authorisation”.6 However, legal reasoning is of limited value since bad laws can be replaced. The federation’s scientific reasoning is also incomplete. In their report they underline the organisational difficulties of an ideal trial—eg, how to choose the best comparative drug, the best dose, and the best indication. These difficulties certainly exist, but we shall never develop the best approach for comparative trials if comparisons are banned from the outset. Drugs shown to work better than placebo might nevertheless be inferior to other drugs for the same indication. The federation’s argument that “Active-control trials cannot replace the experience gathered through in-market medical use, and post-authorisation research” might be acceptable if postmarketing research existed. Many antihypertensive agents have been on the market for years and have not had their effects on morbidity and mortality compared. Unfortunately, in Europe, trials can only be arranged— with few exceptions—if they are of interest to the pharmaceutical industry since, unlike in the USA, there are no agencies with a mandate to support intervention trials. The public-health arguments used by the federation are even vaguer than their scientific and legal ones, and include statements such as: the cost of drug development would rise, it would take longer to make innovative drugs available, incremental research should not be discouraged, new drugs might offer economic advantages, patient

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compliance might be improved, side-effects might be reduced, and patient diversity can be better addressed. In conclusion, the federation’s reasoning consists more of wishful thinking than reality, and does not actually conflict with use of comparative trials. How can incremental research be done without comparisons? How can improved compliance or fewer side-effects of a drug be ascertained in placebo trials? Patient sensitivity to various compounds of the same class probably differs, but what proof exists besides anecdotal reports? The only way to show that patients benefit from a new drug is to show that it is active, whereas other drugs have failed for reasons of efficacy or safety. Finally, economic arguments would be convincing, but new drugs always cost more than old ones. As for innovation, only 60 of the 126 products approved by the CPMP in its first 5 years could be regarded as innovative. In fact, the arguments used by the federation favour the promotion of legislation ensuring a place for comparative studies in drug development. Few therapeutic areas and indications exist, besides rare diseases, for which there is no treatment; in these cases only must placebo be used rather than an active comparative drug. Non-inferiority, equivalence, and superiority Let us therefore assume that comparative trials are the future of marketing authorisations. By contrast with superiority trials, equivalence studies are designed to show that a given difference is not significant, although it might be clinically important.7 Similarly, non-inferiority studies might not show a 10 or 20% difference in drug activity to be significant. Non-inferiority or equivalence trials are frequently used to avoid looking for differences between drugs; the only way to raise the precision of a trial is to recruit more patients. Obviously, more patients are needed for non-inferiority or equivalence trials in which a 2% difference is used rather than 10%. However, the consequence of this approach—even if it is used in a comparative trial—is a high degree of uncertainty about the merits of the drugs tested. At worst, the new drug could induce more adverse effects than the old one, and might be discarded before its effectiveness has been properly ascertained.8 Non-inferiority and equivalence trials raise serious ethical problems, since randomisation exposes patients to unknown risks, harm, or burdens, but presumably offers no more benefit than the other treatments. Even if investigators succeed in confirming the equivalence or non-inferiority of a drug, no advantage is gained by the patient. In such trials, the limits of the acceptable difference (the delta effect), should be established by, or agreed with, ethics committees who should justify their reasoning. Drugs that are presumed to be as effective as those already available can be ethically tested if the trial is used to investigate a potential advantage. Non-inferiority or equivalence trials must prove that the new drug is safer, better tolerated, easier to use, or cheaper than the old one. Health services would regard lower cost as a worthwhile public health advantage. Costs EMEA has no means of establishing a drug price. However, price information should be a factor in drug assessment. Despite regular appeals to take economic aspects into consideration and contain health-care costs, the CPMP works in an ideal world in which there are no financial limits on new drugs.9 A drug may be approved, in exceptional circumstances, without comprehensive test results, if such information is

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VIEWPOINT

impossible to provide at that time.1 These exceptional situations seem to occur rather frequently: 18 of 126 (14%) authorisations were granted in these circumstances in EMEA’s first 5 years. These approvals should be conditional and temporary, have a time limit (3 years should be sufficient), and include a specification of the type of studies needed. Randomised clinical trials of drugs approved in this way would clarify uncertainties about their therapeutic value. Unfortunately, randomised trials of products that have already been authorised are often thought to be unfeasible or unethical, which is possibly why conditional status has so far been revoked for only four products. Prototypes on the market should be replaced as soon as superiority trials show that new comparative drugs are more effective or safer. Observational extensions and equivalence studies provide no useful information for patients, and enlarge the market to include new drugs that are not necessarily any better than old drugs or placebo.

Summary of product characteristics The best way for a physician to obtain objective information about individual drugs is to read the summary of product characteristics, which is a lengthy description that has been prepared, since 1995, by the product manufacturer and the CPMP. However, in these summaries, drugs are described as if they were the only ones on the market; comparisons should be made with other drugs with a similar mechanism of action that are available for the same indications. Comparative information would show whether differences in sideeffects were significant, or just a promotional exercise, and whether responses to a product by patients resistant to a different one are thoroughly documented. Finally, the summary information should reference any differences of opinion about the drug in the scientific community or among regulatory authorities. The summary of product characteristics is seldom made available to physicians, which is one reason for the large number of off-label prescriptions. Therefore, all efforts made by the CPMP to report changes in product summaries are rendered worthless. Distribution of the summary among physicians should be done by national authorities, and it should also be compulsory for pharmaceutical companies to use the summary as their only source of advertising. New drugs approved through the central procedure now have a harmonised summary, but most drugs in Europe still circulate with different, and often divergent, summaries. Great efforts are needed to overcome these discrepancies.

company might also be seeking approval for its product. If a drug is not approved or rejected unanimously, the minority view is lost along the route to making the committee’s opinion on the drug public. Reports of all views in all documents, including the summary of product characteristics and the EPAR (European Public Assessment Report) would enable people to make up their own minds. Although votes are needed to reach a decision at the regulatory level, the majority decision does not necessarily represent the truth.

Mutual recognition The decentralised procedure for approval of new drugs via national authorities conflicts with the EMEA-only centralised procedure. The decentralised system seems to contribute more to the free movement of pharmaceutical products in the European Union than to patients’ interests.10–12 The centralised route is compulsory only for biotechnology products. Thus, for most conventional drug approval applications, the decentralised route, which works on the principle of “mutual recognition” between member states, is possible. Arbitration by the CPMP in cases of disagreement among these countries is frequently avoided by withdrawal of the application from the reluctant country.10 This manoeuvre should not be allowed as it leads to different outcomes in different member states, contrary to what is established for the centralised procedures. The mutual recognition procedure should be a merely methodological, not substantial, alternative to the centralised procedure. Ultimately, abolition of the decentralised procedure would make the approval of new drugs more uniform.

Renewal of marketing authorisation Every 5 years, drugs have to be reviewed to remain on the market.2-9 Industry favours an assessment that is essentially administrative—ie, if a drug were to have no record of serious adverse effects, its authorisation should be automatically renewed. Public health interests would be better served by an updated analysis of the drug’s benefit-risk profile. The 5-yearly review could serve as an occasion to assess whether new drugs have superseded the drug under examination, and whether knowledge of the disease the drug is intended to treat has substantially changed. Effort should be made to clear the market of drugs whose efficacy has never been proved. The EMEA should have a special organisation to collect information on all the drugs on the European market, and should have adequate means not only to store submitted reports, but also to support research on sideeffects and inappropriate drug use.

Transparency CPMP has improved transparency by establishing rules to decide on conflicts of interest, and by making its decisions available through the EMEA website and press releases. However, there is still room for improvement. If a preliminary trend vote within the CPMP is negative, the company concerned is given the chance to accept the result, which generally occurs if the company plans to appeal, or to withdraw the application. Up to December, 2000, there were only four negative opinions, but 49 withdrawals. Information on withdrawn applications is confidential, and no data are made public. Public health interests would be served by publication of such data. Therefore, either no withdrawal should be allowed after preliminary assessment, or the essential characteristics of any drug whose application has been withdrawn should be reported. This information might also be very important for countries outside the European Union, where the

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Orphan drugs Special attention is required for orphan drugs, which are of no financial interest to pharmaceutical companies because their target population is small. In the USA, an orphan drug act was passed in 1983; a similar law was approved in Europe only at the end of 1999.13 Designation of orphan drugs is made by the Committee on Orphan Medicinal Products, which is a body of representatives from the 15 European Union member states; the dossier is assessed by the CPMP. Among other advantages, orphan drugs will have 10 years of exclusivity after approval. We must welcome the fact that now a minority of patients might begin to have some hope about new therapies. However, there are at least three important points to solve. European law does not allow any financial incentives for orphan drug development; such incentives are essential, especially for

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very rare diseases. The European Union’s fifth framework programme of research might accommodate some cases, but a specific monetary fund is a necessary complement to the law. Furthermore, dossiers on orphan drugs are obviously less complete than those for drugs for common diseases, which can lead to unsatisfactory regulatory outcomes.14 Therefore, methodological research needs to be promoted, to ensure that reliable results are obtained from necessarily small groups of patients. To follow entire cohorts in rare disease drug trials should be a postmarketing commitment. Finally, to break the exclusivity agreement for an orphan drug, a competitor product should have to prove different from the original. If the competitor is similar, clinical superiority should be shown.13 Such similarity should be discussed in terms of mechanism of action, independently from chemical structure. This view ensures better protection of exclusivity for the original drug. Clinical superiority implies the need for comparative studies showing higher efficacy, better safety, or some clinical advantage for the patient. In conclusion, centralisation of at least one part of the marketing authorisations at the EMEA is satisfactory, and should be gradually increased, with the aim of unifying the approval, monitoring, and policies on medicinal products, including pharmacovigilance and review of drug use. The institutional location of EMEA should be changed so it reports to the directorate of public health, not industry. Approval of new drugs must involve comparative assessments. More criticism is needed in the approval of new drugs. To defend patients’ interests, companies cannot be allowed to release drugs with the sole aim of obtaining a slice of the market. The increasing power of the pharmaceutical industry requires an equally strong counterpart to ensure that drugs continue to be beneficial to patients, and are not just a profitable business.

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Contributors SG and VB respectively act as CPMP member and expert. The personal views they express in this paper do not commit the CPMP or the EMEA as such.

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Council regulation (EEC) no 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products. Off J Eur Comm 1993; no L 214 of Aug 24: 1. European Commission. The rules governing medicinal products for human use: notice to applicants—procedures for marketing authorisation. European Communities 1998, 2A: 51–72. European Commission. The rules governing medicinal products for human use: notice to applicants—presentation and content of the dossier. European Communities 1998, 2B: 24–174. European Commission. The rules governing medicinal products for human use: pharmaceutical legislation. European Communities 1998: 1–287. International Conference for Harmonisation. Topic E10: note for guidance on choice of control groups for clinical trials. http://www.emea.eu.int. Document id: CPMP/ICH/364/96 adopted July 27, 2000 (accessed on June 6, 2001). European Federation of Pharmaceutical Industries and Associations (EFPIA). Evolution of standards. http://www.efpia.org (accessed on June 6, 2001) Committee for Proprietary Medicinal Products. Points to consider on switching between superiority and non-inferiority. http://www.emea.eu.int. Document id: CPMP/EWP/482/99 adopted July 27, 2000 (accessed on June 6, 2001). Bertele’ V, Torri V, Garattini S. Inconclusive messages from equivalence trials in thrombolysis. Heart 1999; 81: 675–76. Council directive of 89/105/EECof 21 December 1988 relating to the transparency of measures regulating the pricing of medicinal products for human use and their inclusion in the scope of the national health insurance systems. Off J Eur Comm 1989; no L 40 of Feb 11: 8. Council directive of 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products. Off J Eur Comm 1965; no L 22 of Feb 9: 369. Council directive of 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products. Off J Eur Comm 1975; no L 147 of June 9: 13. European Commission. The rules governing medicinal products for human use: notice to applicants—procedures for marketing authorisation. European Communities 1998, 2A: 15–38. Regulation (EC) no 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products. Off J Eur Comm 2000; no L 018 of Jan 22: 1–5. Garattini S, Bertele’ V. Multicentre clinical trials. Lancet 1999; 353: 930.

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